Influenza, commonly referred to as flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae (the influenza viruses). Influenza spreads around the world in seasonal epidemics, resulting in the deaths of between 200,000 and 500,000 to people every year, up to millions in some pandemic years. The development of effective antiviral medicines is hampered by the exceptionally high mutation rates of influenza virus. Therefore, in order to be successful, new drugs should target the molecular mechanisms specific to the proliferation of the virus.
Antiviral drug such as Oseltamivir is an orally active neuraminidase inhibitor, which has been widely used for the treatment of H5N1 avian influenza as well as a recent outbreak of H1N1 swine flu. The drug is sold under the trade name Tamiflu, and is taken orally in capsules or as a suspension. It has been used to treat and prevent influenza A virus and influenza B virus infection in over 50 million people since 1999. The anti-influenza drug was initially discovered by Gilead Sciences and subsequently licensed to Roche for production.
The initial synthesis of Tamiflu, developed by Gilead Sciences, employs (−)-quinic acid as the starting material, alternatively, shikimic acid was used for the commercial production. Large quantities of (−)-shikimic acid are obtained by extraction from star anise plant which is grown in China by a biocatalytic process which uses glucose as carbon source. The process is described below in Scheme 1:

However, the supply of (−)-shikimic acid of consistent purity is problematic due to seasonal and geographical constraints.
U.S. Pat. No. 7,531,687 (Applicant—Roche) relates to a process for the conversion of Shikimic acid to oseltamivir (I), and optionally to an acid addition salt, via the intermediate phosphoramide VII. The process is described in Scheme 2 below:

The process comprises the steps of (step 1) converting an alkyl shikimate ester (III) to the corresponding tris-mesylate IV by reacting III with methanesulfonyl chloride the presence of an aprotic organic solvent and an organic base; (step 2) stereoselectively displacing the mesyloxy substituent on C-3 with azide in an organic solvent optionally in the presence of water and a phase transfer catalyst to afford V; (step 3) contacting V with a trialkylphosphite in an inert organic solvent to induce a Staudinger reaction and provide the aziridine (VI); (step 4) opening the aziridine by contacting VI with a Lewis acid in the presence of a first alcohol to form VII; (step 5a) contacting VII with a strong acid in a second alcoholic solvent to hydrolyze of the phosphoramidate and afford the amine VIII-1; (step 6a) contacting VIII-1 with an acylating agent and a base to afford VIII-2; (step 7a) contacting VIII-2 with a azide in a second organic solvent and in the presence of a third alcohol to displace the remaining mesyloxy group to afford IX and (step 8) contacting IX with a reducing agent to afford oseltamivir (I) which is optionally converted to a pharmaceutically acceptable salt.
Article titled “The Synthetic Development of the Anti-Influenza Neuraminidase Inhibitor Oseltamivir Phosphate (Tamiflu®): A Challenge for Synthesis & Process Research” by Karf, Trussadi et. al in CHIMIA International Journal for Chemistry (2004), Volume: 58, Issue: 9, Pages: 621-629 discloses synthesis of Oseltamivir Phosphate from naturally available (−)-shikimic acid as a chiral pool starting material. The process is depicted in Scheme 3 below:

An article titled “Short Enantioselective Pathway for the Synthesis of the Anti-Influenza Neuramidase Inhibitor Oseltamivir from 1,3-Butadiene and Acrylic Acid” by E. J. Corey published in J. Am. Chem. Soc., 2006, 128 (19), pp 6310-6311 discloses synthesis of Oseltamivir from 1,3-Butadiene and acrylic Acid as shown in Scheme 4.

Article titled “Second Generation Catalytic Asymmetric Synthesis of Tamiflu: Allylic Substitution Route” by Masakatsu Shibasaki et. al in Org. Lett., 2007, 9 (2), pp 259-262 discloses Catalytic asymmetric synthesis of Tamiflu. After the catalytic enantioselective desymmetrization of meso-aziridine 3 with TMSN3, using a Y catalyst (1 mol %) derived from ligand 2, an allylic oxygen function and C1 unit on the CC double bond are introduced through cyanophosphorylation of enone and allylic substitution with an oxygen nucleophile (Scheme 5).

Article titled “A Practical Synthesis of (−)-Oseltamivir” by Fukuyama et. al (Part I) in Angew. Chem. Int. Ed. 2007, 46, 5734-5736 discloses preparation of Oseltamivir from pyridine and acrolein. The asymmetric Diels-Alder reaction with acrolein 3 is carried out with the McMillan catalyst to the aldehyde 4 as the endo isomer which is oxidized to the carboxylic acid 5 with sodium chlorite. The process is given below in Scheme 6

In the article “A Concise Synthesis of (−)-Oseltamivir” by Barry M. Trost, Ting Zhang in Angew. Chem. Int. Ed. 2008, 47, 1-4, synthesis of Oseltamivir is disclosed which is given below in Scheme 7:

Since control of stereochemistry is important, as the molecule has three stereo centers, the prior art processes use costly chiral reagents or catalysts to obtain the desired enantioselectivity. Furthermore, the commercial production of Oseltamivir from the biomolecule shikimic acid or from its enantiomer is restricted by limited supply of the plant worldwide.
Due to the limited supply of shikimic acid, searches for alternative synthetic routes preferably skipping shikimic acid are underway. Further, though Oseltamivir is not a complex molecule yet its practical synthesis on a large scale, enough to guard against an influenza pandemic, presents a formidable challenge.
In view of the above, there remains a need to provide a high-yielding enantioselective approach towards the synthesis of Anti-Influenza Agent Oseltamivir from readily available and less expensive starting materials.